RELA tunes innate-like interferon I/III responses in human T cells

Area of Science:

• Immunology
• Molecular Biology
• Cell Biology

Background:

• Innate immune cells utilize cGAS-STING signaling for type I/III interferon (IFN) production, crucial for antiviral defense.
• Control mechanisms for IFN-I/III expression in adaptive immune cells, particularly T cells, remain largely unelucidated.

Purpose of the Study:

• To investigate the mechanisms controlling type I/III interferon production in human T cells.
• To identify factors that confer innate-like IFN production capabilities to adaptive immune cells.

Main Methods:

• Analysis of cGAS-STING signaling pathways in CD4+ T cells compared to dendritic cells and macrophages.
• Investigation of the role of RELA, including its lysine residues, in regulating IFN-I/III expression.
• Assessment of positive feedback loops involving cGAS and IRF7.
• Experimental manipulation using RELA, IRF3, and DNA demethylation to enhance IFN production.

Main Results:

• CD4+ T cells exhibit stunted IFN-I/III responses despite intact cGAS-STING signaling.
• Lysine residues on RELA modulate baseline and STING-stimulated IFN-I/III responses in T cells.
• IFN-I/III production in T cells requires positive feedback from cGAS and IRF7.
• Combined manipulation of RELA, IRF3, and DNA demethylation elevated T cell IFN-I/III production to levels seen in dendritic cells.

Conclusions:

• A transcriptional rheostat orchestrated by RELA endows human T cells with innate-like IFN-I/III production capabilities.
• Modulating innate-like functions in T cells offers potential for enhanced antiviral defense against HIV and improved tumor cell elimination by CAR T cells.